There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching three interrelated goals: 1)Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes; 2)Ascertainment of the consequences of overexpressing candidate genomic regions identified in human tudies; 3) Elucidation of gene elements yielding cell-type specific expression and trans-synaptic gene regulation. Dopaminergic systems' involvement in central mechanisms of reward and reinforcement, and involvement of pre- and post-synaptic opioid peptide systems in the effects of opiate drugs has led to continuing focus on these systems during this year. Previoiusly-reported failure to reduce cocaine reward in DAT, SERT or NET knockout mice has led to expanded efforts to study combined transporter knockouts. Each of these assessments has provided novel data concerning the relationship between expression of each of these gene products at normal levels and drug-induced behavioral changes. In particular, studies of mice without combinations of DAT, VMAT2, SERT, NET and/or dopamine and serotonin receptor subtypes provides striking evidence for mechanisms of cocaine and amphetamine reward, monoaminergic involvement in mechanisms of sleep/wake regulation, and apparent monoamine transporter involvement in cocaine's aversive properties. Combined transporter deletions can thus either substantially enhance cocaine reward or substantially reduce it, as measured in conditioned plcae preference paradigms. DAT knockouts can complement the cocaine reward alterations induced by 5HT1B knockout. Interestingly, normally-nonrewarding selective NET and SERT blockers gain rewarding properties in mice with deletions of other monoaminergic transporters. These studies contribute to a novel three-site model for combined rewarding and aversive properties of psychostimulants developed in the Branch during this year.